Posts Tagged ‘belatacept’

In the last few years, thanks to the development of anti-rejection drug therapies, outstanding breakthroughs in short-term outcomes have been achieved among organ transplant patients. We first introduced you to belatacept on our blog in September of 2010, while the medication was being studied by our team of doctors and researchers. Then in June of last year, we announced the FDA’s approval of belatacept and its confirmed ability to provide a less toxic alternative to the standard anti-rejection medications, including calcineurin inhibitors like cyclosporine.

Even with these developments, though, significant challenges remain for patients over the long term with organ rejection and drug toxicity that often leads to cardiovascular disease, infection or cancer.
To help overcome these challenges, a new $20 million grant has been bestowed upon Emory from the National Institute of Health to allow physician/researchers to develop better treatments for organ transplant recipients that help avoid both organ rejection and drug toxicity. The new grant builds upon more than 18 years of groundbreaking research by Emory scientists—such as the investigation into belatacept—that has already significantly advanced the transplant field.

Dr. Larsen

“Despite tremendous advances in immune drug therapy, the fact remains that organ recipients still must take immunosuppressant drugs over their lifetimes,” says Chris Larsen, MD, PhD, executive director of the Emory Transplant Center and principal investigator of the new grant. “Improvement in these transplant drugs is still a critical need for avoiding acute and late-stage rejection. Ultimately, we want to improve overall health while reducing cost through improved outcomes with fewer drugs.”

In addition to Dr. Larsen, project leaders from the Emory Transplant Center will include Allan D. Kirk, MD, PhD, scientific director of the Emory Transplant Center and a Georgia Research Alliance Eminent Scholar; Leslie Kean, MD, PhD, Emory associate professor of pediatrics and director of the Pediatric Bone Marrow Transplant Division of the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Stuart J. Knechtle, MD, surgical director of the liver transplant program at Emory Transplant Center and Children’s Healthcare of Atlanta, and Andrew Adams, MD, PhD, assistant professor of surgery.

“The most important feature of this award is its support for multiple investigators attacking the problems of immunosuppression from different but complementary angles,” says Kirk. “The team science approach is the best way to get results to our patients.”

Several projects funded by the new grant will aim to develop more effective transplant drugs and strategies to avoid immunosuppressant drugs altogether.

An additional project will develop strategies to overcome immune sensitization in patients who have had previous transplants, pregnancies or blood transfusions. These patients often are not candidates for transplant because of their increased risk of rejection.

For more information about the Emory Transplant Center, its research projects and clinical programs please use the Related Resources links below.

A life free from taking anti-rejection medications post-transplant…is it possible? After transplant, patients must take multiple medications to keep their bodies from rejecting the new organ. The side effects of these immunosuppressant drugs, for many, can be grueling. Side effects range from fatigue to high blood pressure to increased risk of infection. Researchers are currently evaluating whether it’s possible for kidney transplant patients to avoid use of immunosuppressant drugs post transplant. They’ve found that it’s possible that by not only transplanting the living donor organ but also some of the donor’s immune producing cells, it may be possible to deceive the recipient’s immune system into accepting the new organ as its own.

To evaluate the likelihood of decreased reliance on immunosuppressant drugs for kidney transplant patients, researchers collect immune system-producing stem cells and other immunity cells from the living donor’s bloodstream. They infuse transplant patients with radiation and medications to wipe out part of their own bone marrow. This allows the donated cells to squeeze in and create a sort of ‘mixed’ immunity that prevents rejection. In essence, a kidney transplant patient would also be receiving a bone marrow transplant.

Dr. Kenneth Newell

At the Emory Transplant Center, researcher Dr. Kenneth Newell, is compiling a registry of kidney recipients who somehow survive despite quitting the pills on their own because they couldn’t afford them or because of side effects – a truly rare case. Thus far, Dr. Newell has discovered about three dozen of these cases. The research team at Emory is testing these patients for biological markers that might explain why they fared well and who else is a good candidate. This may provide clues that a completely separate part of the immune system plays a role in organ rejection/acceptance.

In the meantime, the Food and Drug Administration (FDA) approved the drug belatacept (Nulojix®) for the prevention of graft rejection after kidney transplants. This is the first time a new class of drugs has been developed for transplant since the 1990s. Belatacept has the potential to improve and simplify the medication regimens of kidney transplant recipients, being a less toxic alternative to calcineurin inhibitors, with fewer side effects such as high blood pressure, high cholesterol, kidney toxicity and diabetes. It is now being offered at the Emory Transplant Center, where Emory physicians played a role in discovering this new drug.

After decades of research and testing, the FDA approves belatacept, and a new class of transplant drugs first discovered by Emory doctors.

Back in September, Dr. Christian P. Larsen, Director of the Emory Transplant Center, shared a story with you here on our blog about belatacept, a new medication that was being studied to determine its ability to help block the immune system from graft rejection after kidney transplants. It’s been less than a year since we shared that story on belatacept with you, and since that time, the FDA has now approved belatacept for use for that exact purpose.

Dr. Christian Larsen, Director of Emory Transplant Center

Dr. Thomas Pearson, Surgical Director, Kidney Transplant Program

Since the early 1990s, Emory surgeon-scientists Christian P. Larsen, MD, DPhil and Thomas C. Pearson, MD, DPhil have been searching for ways to promote immune tolerance of a transplanted organ. In collaboration with other Emory researchers and researchers at Bristol-Myers Squibb, they played a leading role in discovering belatacept and driving its development. The recent FDA approval of use of belatacept is the first time a new class of drugs has been developed for transplant since the 1990s.

So what led to this approval of a new class of drugs? From a research perspective, in the 1990s, Larsen and Pearson found that CTLA4-Ig, a fusion protein of which belatacept is a modified type, could control graft rejection in mice, but found that it didn’t work as well in non-human primates. Bristol-Myers Squibb researchers then developed a panel of hundreds of modified forms of CTLA4-Ig, and sifted through the mutated proteins to find two that could make CTLA4-Ig bind tighter to its target and work more effectively. Larsen and Pearson then showed that the enhanced version could prevent graft rejection in a non-human primate model for kidney transplant at Yerkes Research Center.

Once the determination was made that modified versions of the CTLA4-lg fusion proteins could work to prevent graft rejection on primates, belatacept was developed and tested. In two parallel studies with more than 1,200 participants over two years, patients taking belatacept had similar graft survival rates to those taking the calcineurin inhibitor cyclosporine, while maintaining higher kidney function and lower blood pressure and cholesterol. In addition, belatacept can be given every few weeks, in contrast to calcineurin inhibitors, which must be taken twice a day.

There is still room for improvement, though. Compared with cyclosporine-treated patients, belatacept-treated patients had a higher rate of early acute rejection – a temporary flare-up of the immune system against the donated kidney. However, in most cases the acute rejection was successfully treated with drugs and did not lead to graft failure. The Emory Transplant Center team is researching approaches to reduce this risk.

“Our goal is to achieve a normal life span for kidney transplant patients, and have them survive dialysis-free,” Larsen, Director of the Emory Transplant Center, says. “We believe belatacept can help us move toward that goal.”

Clinical trials are now also being conducted to determine if belatacept will have similar positive outcomes on liver transplant and pancreatic islet transplant patients.

For more information on belatacept, you can check out the video below. If you have additional questions, leave them in the comments for Dr. Larsen or Dr. Pearson and we’ll make sure they see them and give you a response!

Today, kidney transplantation provides patients with invaluable benefits—it prolongs lifespan and restores vitality and health. However, this hasn’t always been the case. As recently as the 1980s, results of transplants were fairly poor, and kidneys were often lost from rejection. In 1983, the cyclosporine class of drugs entered the equation, revolutionizing transplantation. Short-term outcomes improved greatly, and we expected most of our patients to survive with a functioning graft—90% of them at the 1-year mark.

Unfortunately, while cyclosporine is ideal for short-term outcomes, it causes many side effects that affect long-term outcomes in patients. Cyclosporine is toxic to the kidney—over time, this causes excess scarring and eventually even leads to loss of kidney function.

In approximately one-third of patients, cyclosporine causes post-transplant diabetes, requiring most patients to take blood pressure lowering medications. Additionally, most must take medications to lower their cholesterol. (High blood pressure and increased cholesterol counts are both side effects of cyclosporine.) Ultimately, patients must take the anti-rejection drugs along with a host of other drugs to combat the side effects, all of which can lead to death from cardiovascular disease. On average, the kidney transplant patient survival rate is only 8-10 yrs, which is clearly short of what we’d like to see.

Sufficed to say, there’s been a tremendous need for better drugs to prevent rejection in kidney transplants, without causing life-threatening side effects.

Introducing Belatacept

When kidney patients suffer from transplant rejection, the immune system essentially recognizes the new kidney as a foreign object, causing lymphocytes and T-cells to attack, and generating immune damage to the transplant. Consequently, we introduce drugs to dampen the immune system. The issue with cyclosporine is that it doesn’t just affect the immune response; it hits several other targets throughout the body, causing the negative side effects. Fortunately, there’s hope on the horizon with a newer drug called belatacept.

Like Cyclosporine, belatacept blocks the immune system from transplant rejection. However, the target of belatacept is only expressed in the immune system, so it suppresses undesired immune responses of rejection without the off target side effects (e.g. high blood pressure, increased cholesterol and diabetes) seen with Cyclosporine. We refer to these off-target responses as “costimulatory signals”.

In transplantation, our goal is to achieve a normal life span for our patients, and to ideally have them move on from surgery dialysis-free. At Emory, we’ve dedicated years to developing new and improved therapies that avoid major complications from kidney transplants, including cardiovascular issues, infections and malignancies.

Recent belatacept studies indicate that this drug could quite possibly help us in achieving these goals. Over 1400 patients have been studied with belatacept’s use in kidney transplant, and the results continue to be extremely promising. Further, the drug could conceivably have advantages for other types of organ transplantation, including liver, heart, lung, and intestinal.

Do you have any questions about belatacept, or about kidney transplantation in general? If so, please let me know in the comments.

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